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Role of G9a methyltransferase in the dna damage response signal
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Rodriguez-Colon, Lizahira. Role of G9a methyltransferase in the dna damage response signal. Retrieved from https://doi.org/doi:10.7282/T3JS9TW0

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TitleRole of G9a methyltransferase in the dna damage response signal
NameRodriguez-Colon, Lizahira (author); Xia, Bing (chair); Pine, Sharon (internal member); Ganesan, Shridar (internal member); Langer, Jerome (outside member); Rutgers University; School of Graduate Studies
Date Created2018
Other Date2018-05 (degree)
SubjectPharmacology, Cellular and Molecular, DNA repair
Extent1 online resource (viii, 115 p. : ill.)
DescriptionDNA damage induces a choreographed set of local changes in histone modifications which leads to efficient recruitment of DNA repair factors. The regulation of these chromatin modifications at DNA breaks is critical to maintain genome integrity. Recent studies in our lab have identified a role for G9a methyltransferase in regulating DNA repair. The overall aim of this project was to elucidate how G9a activity regulates this pathway and to identify the effects of its inhibition in this process. It was shown that G9a localizes to sites of DNA damage in an ATM-dependent fashion and that inhibition of G9a activity affects early recruitment of multiple DNA repair factors. We found that catalytic inhibition of G9a using UNC0638 results in increased ATM activation. This led to increased "spreading" of pH2AX and MDC1 signals seen at regions of localized DNA breaks induced by UV-laser scissors, which was dependent upon ATM activation. This was also associated with increased levels of H3K36me2 and H3K56Ac. Biochemical data showed that G9a interacts and regulates HDAC1/2 activity during the DNA damage response. G9a inhibition led to decreased HDAC1 methylation, and increased ATM acetylation. These data suggest that G9a activity regulates the extent of ATM activation induced by DNA breaks and is required for efficient recruitment of downstream DNA repair factors. Overall our data suggests that G9a plays a critical role in regulation of ATM-dependent signaling during the DNA damage response and raises the possibility of using G9a inhibitors in the clinical setting as part of novel cancer therapies.
NotePh.D.
NoteIncludes bibliographical references
Noteby Lizahira Rodriguez-Colon
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3JS9TW0
Languageeng
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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